NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth.

Publication date: Jan 15, 2020

Constitutive activation of STAT3 can play a vital role in the development of melanoma. STAT3-targeted therapeutics are reported to show efficacy in melanomas harboring the BRAFV600E mutant and also in vemurafenib-resistant melanomas. We designed and synthesized a series of substituted nitric oxide (NO)-releasing quinolone-1,2,4-triazole/oxime hybrids, hypothesizing that the introduction of a STAT3 binding scaffold would augment their cytotoxicity. All the hybrids tested showed a comparable level of in vitro NO production. 7b and 7c exhibited direct binding to the STAT3-SH domain with IC of ? 0.5 ?M. Also, they abrogated STAT3 tyrosine phosphorylation in several cancer cell lines, including the A375 melanoma cell line that carries the BRAFV600E mutation. At the same time, they did not affect the phosphorylation of upstream kinases or other STAT isoforms. 7c inhibited STAT3 nuclear translocation in mouse embryonic fibroblast while 7b and 7c inhibited STAT3 DNA-binding activity in the A375 cell line. Their anti-proliferating activity is attributed to their ability to trigger the production of reactive oxygen species and induce G1 cell cycle arrest in the A375 cell line. Interestingly, 7b and 7c showed robust cell growth suppression and apoptosis induction in two pairs of BRAF inhibitor-na”ive (-S) and resistant (-R) melanoma cell lines containing a BRAF V600E mutation. Surprisingly, MEL1617-R cells that are known to be more resistance to MEK inhibition by GSK1120212 than MEL1617-S cells exhibit a similar response to 7b and 7c.

Kaoud, T.S., Mohassab, A.M., Hassan, H.A., Yan, C., Van Ravenstein, S.X., Abdelhamid, D., Dalby, K.N., and Abdel-Aziz, M. NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth. 25355. 2020 Eur J Med Chem (186):

Concepts Keywords
Apoptosis Genentech
BRAF Chloroarenes
BRAF Inhibitor Melanoma
Cytotoxicity Tyrosine kinase inhibitors
DNA Cancer treatments
Fibroblast Cancer
Hybrids Clinical medicine
Isoforms A375 melanoma
MEK Vital melanoma STAT3
Melanoma Show efficacy melanomas
Melanomas BRAF mutant melanoma
Mutant BRAF
Mutation Vemurafenib
Nave V600E
Nitric Oxide Targeted therapy
Oxime Apoptosis
Oxygen DNA binding


Type Source Name
disease MESH melanoma
pathway KEGG Melanoma
disease MESH growth
drug DRUGBANK Vemurafenib
drug DRUGBANK Nitric Oxide
drug DRUGBANK 1 2 4-Triazole
drug DRUGBANK L-Tyrosine
disease MESH cancer
pathway KEGG Apoptosis


Original Article

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